Diphenidol (α,α-diphenil-1-piperidinebutanol) is a drug which has been used for a long time as an antiemetic and anti vertigo agent. The base of the antiemetic effect is found in the brain, specifically in the action sites at the chemoreceptor trigger zone in the area postrema. Likewise, its anti vertigo effect is attributed to its action in the vestibular apparatus (Leung et al., Pharmacological Reports. 2012, 64, 739-744). Diphenidol hydrochloride is the most used salt of this active principle.
Diphenidol is indicated to prevent and control nausea and vomiting caused by diseases affecting kidneys, liver, gall bladder and gastrointestinal tract, as well as those caused by labyrinth alterations, malignant neoplasm, radiation therapy, emetic agents (such as drugs and food intoxication), post-surgical studies, movement disease, among others.
Currently, diphenidol pharmaceutical forms commercially available in the market are immediate release solutions and tablets.
The drug release system plays a fundamental role in the control of the pharmacological effect, since it influences the pharmacokinetic profile, the drug release speed, on the site and duration of the pharmacological action, as well as on the side effects profile. An optimum drug release system assures this is available at the action site, with a suitable duration of the pharmacological action. Thus, the drug concentration being released in the suitable site has to be over a minimum effective concentration (MEC) and under a minimum toxic concentration (MTC) (Perri, Y. and Rades, T., Pharmaceutics drug delivery and targeting. Pharmaceutical Press, 2010).
While the action site of the majority of the drugs is not the plasma, drug concentrations are basically determined in said plasma since there is a direct relationship between drug plasma concentrations and the action site drug concentrations, which in turn is correlated to pharmacological effect and pharmacological action. Reaching the desired drug concentration in plasma and the action site depends, among other factors, on dosage frequency, drug clearance rate, administration route, and drug release system used (Perri and Rades, 2010).
The oral administration route is the most used, and the release forms of the drug administered by this route are immediate release and modified release, classified in turn as sustained release and delayed release. In the immediate release, the drug is immediately released after its administration; as the drug action time is limited to the time when the drug concentration is above the MEC, if the drug has a short half life then the re-administration range will be short and, consequently, it will require a frequent drug administration, which has a potential risk to cause low adhesion to the treatment from the patient and, therefore, an inadequate therapeutic effect. On the other hand, sustained release systems allows the releasing of the drug for extended periods of time, being able to reduce dosage frequency (Jones, D., Pharmaceuticals dosage form and design. Pharmaceutical press, 2008; Aulton, M. E., Aulton's Pharmaceutics. The design and manufacture of medicines. Churchill Linvingston Press, 2007). However, not all drugs are suitable candidates for sustained release medicaments, since drug characteristics such as dose, efficacy, solubility, stability, absorption, and presystemic and systemic metabolism have to be considered (Perri and Rades, 2010).
Diphenidol hydrochloride is well absorbed after oral administration, reaching a maximum time in plasma concentrations between 1.5 and 3 hours, while the half life is 4 hours (Hernández at al, Development of an HPLC method for determination of diphenidol in plasma and its application in an oral multi-dose bioequivalence study in a healthy female Mexican population. J. Pharm. Biomed. Anal., 2005, 38:746-750). This is the reason why the use of immediate release solutions and tablets represents certain disadvantages for the patient, for example, having to perform four intakes daily, one every 6 hours, in order to maintain the plasma concentration at systemic level in 24 hours; this intake frequency, which is established under medical prescription, may cause an overdosing or intake missing.
In order to overcome these drawbacks, modified release pharmaceutical forms have been developed.
For example, U.S. Pat. No. 5,368,861 describes a unitary preparation, which may comprise diphenidol hydrochloride as an active principle. This unitary preparation comprises a fast release portion, being used to assure the therapeutic level of a drug in a short period of time after its administration, and a sustained release portion. The preparation of this patent has, since it is in an aqueous medium, a fast disintegration of the fast release portion and it can maintain a therapeutic level of the drug in question in a short period of time after the administration.
On the other hand, U.S. Pat. No. 7,976,871 describes a dosage form comprising: a) particles in a micromatrix containing a highly soluble active ingredient and one or more hydrophobic agents to control the release; and b) a coating of the particles in the micromatrix with one or more hydrophobic agents to control the release. The dosage form may also include, optionally, one or more excipients commonly used in oral pharmaceutical formations. Diphenidol is included among the high solubility active ingredients capable of being employed in an amount lower than or equal to 1500 mg, and it may be present as a free base form or as a pharmaceutically acceptable salt. The dosage form can be made in a tablet form, and it is administered to the patient once or twice a day only. However, the process for obtaining a modified release system through a micromatrix has the drawback that numerous steps are required, such as the matrix formation, and in some cases the coating of the resulting particles, which rises the process costs.
According to the above, it may be appreciated that the modified release pharmaceutical forms known in the state of the art can be used for a great amount of active principles. However, none of them allows obtaining a pharmaceutical composition specifically designed for diphenidol, which takes its particular characteristics into account, and which results truly useful and effective.